Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia

Introduction: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy. Methods: Patients ≥60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m2 CIV on days 1-7), and DNR (35 mg/m2 [cohort 1] or 45 mg/m2 [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR. Results: Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m2) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m2 DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive. Conclusion: Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m2. This regimen is being further evaluated in phase III trials.</p

Pessaries in multiple pregnancy as a prevention of preterm birth: the ProTwin Trial

Contains fulltext : 79491.pdf (publisher's version ) (Open Access)BACKGROUND: Multiple pregnancies are at high risk for preterm birth, and therefore an important cause of infant mortality and morbidity. A pessary is a simple and potentially effective measure for the prevention of preterm birth. Small studies have indicated its effectiveness, but large studies with sufficient power on the subject are lacking. Despite this lack of evidence, the treatment is at present applied by some gynaecologists in The Netherlands. METHODS/DESIGN: We aim to investigate the hypothesis that prophylactic use of a cervical pessary will be effective in the prevention of preterm delivery and the neonatal mortality and morbidity resulting from preterm delivery in multiple pregnancy. We will evaluate the costs and effects of this intervention. At study entry, cervical length will be measured. Eligible women will be randomly allocated to receive either a cervical pessary or no intervention. The cervical pessary will be placed in situ at 16 to 20 weeks, and will stay in situ up to 36 weeks gestation or until delivery, whatever comes first.The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 7.2% without to 3.9% with a cervical pessary, using a two-sided test with an alpha of 0.05 and a power of 0.80. DISCUSSION: This trial will provide evidence on whether a cervical pessary will decrease the incidence of early preterm birth and its concomitant bad neonatal outcome in multiple pregnancies. TRIAL REGISTRATION: Current Controlled Trials: NTR 1858

Implementation of the external cephalic version in breech delivery. Dutch national implementation study of external cephalic version

<p>Abstract</p> <p>Background</p> <p>Breech presentation occurs in 3 to 4% of all term pregnancies. External cephalic version (ECV) is proven effective to prevent vaginal breech deliveries and therefore it is recommended by clinical guidelines of the Royal Dutch Organisation for Midwives (KNOV) and the Dutch Society for Obstetrics and Gynaecology (NVOG). Implementation of ECV does not exceed 50 to 60% and probably less.</p> <p>We aim to improve the implementation of ECV to decrease maternal and neonatal morbidity and mortality due to breech presentations. This will be done by defining barriers and facilitators of implementation of ECV in the Netherlands. An innovative implementation strategy will be developed based on improved patient counselling and thorough instructions of health care providers for counselling.</p> <p>Method/design</p> <p>The ultimate purpose of this implementation study is to improve counselling of pregnant women and information of clinicians to realize a better implementation of ECV.</p> <p>The first phase of the project is to detect the barriers and facilitators of ECV. The next step is to develop an implementation strategy to inform and counsel pregnant women with a breech presentation, and to inform and educate care providers. In the third phase, the effectiveness of the developed implementation strategy will be evaluated in a randomised trial. The study population is a random selection of midwives and gynaecologists from 60 to 100 hospitals and practices. Primary endpoints are number of counselled women. Secondary endpoints are process indicators, the amount of fetes in cephalic presentation at birth, complications due to ECV, the number of caesarean sections and perinatal condition of mother and child. Cost effectiveness of the implementation strategy will be measured.</p> <p>Discussion</p> <p>This study will provide evidence for the cost effectiveness of a structural implementation of external cephalic versions to reduce the number of breech presentations at term.</p> <p>Trial Registration</p> <p>Dutch Trial Register (NTR): 1878</p

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings

Barriers and Facilitators for the Use of a Medical Mobile App to Prevent Work-Related Risks in Pregnancy: A Qualitative Analysis

BACKGROUND: The number of women participating in the labor market in Europe has increased over the last several decades. At the same time, there is growing evidence that certain conditions of employment during pregnancy may have a negative influence on pregnancy outcomes. In order to better inform pregnant women, we aim to develop an app to help assess the health risk as a result of personal and work-related factors and provide personal advice for these women and their health care providers. OBJECTIVE: The aim of this study was to compose a thematic overview of the perceived facilitators and barriers according to pregnant women, medical professionals, and employers for the use of a mobile app in obstetrical care to prevent occupational-related pregnancy complications. METHODS: Two multidisciplinary focus group meetings with in total 14 participants were conducted with pregnant women, occupational physicians, general practitioners, midwives, obstetricians, and representatives of trade unions and employer organizations. Transcripts were analyzed by qualitatively coding procedures and constant comparative methods. RESULTS: We identified 24 potential facilitators and 12 potential barriers for the use of the app in 4 categories: content of the app, the app as a mean to provide information, ease of use, and external factors. The 3 main facilitators identified were the need for a good interaction between the app and the user, apps were viewed as a more practical source of information, and the information should be understandable, according to the existing guidelines, and well-dosed. The 2 main barriers for use were extensive battery and memory use of the smartphone and sending frequent push notifications. CONCLUSIONS: The results of this study are important considerations in the developing process of a medical app implementing a guideline or evidence-based information in practice

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of (14)C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t(max) 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 +/- 0.095 mug/ml (mean +/- S.D., n = 4) for imatinib and 0.115 +/- 0.026 mug/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 +/- 0.9 h for imatinib, 20.6 +/- 1.7 h for CGP74588, and 57.3 +/- 12.5 h for (14)C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC(0-24 h) (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively